1. Field of the Invention
The invention relates to chemically modified hyaluronic acid and cross-linked derivatives thereof.
2. Description of the Related Art
Hyaluronic acid (HA) is a viscoelastic biomaterial composed of repeating disaccharide units of N-acetyl-D-glucosamine (GlcNAc) D-glucuronic acid (GlcUA). ##STR1##
HA is a major component of the extra-cellular matrix and participates in a number of important biological processes such as cell mobility, cell differentiation, wound healing and cancer metastasis. Highly purified high molecular weight hyaluronate is used in viscosurgery and viscosupplementation and HA is frequently used as an aid in ophthalmic surgery. The use of hyaluronate is also a potential therapy for osteoarthritis in humans.
In the past, efforts have been directed at chemical modifications of hyaluronate targeting hydroxyl and carboxyl functionalities to obtain specific biomedical polymers. U.S. Pat. Nos. 4,582,865 and 4,713,448 to Balasz and Leshchiner describe respectively, cross-linking HA by reaction with divinyl sulfone and cross-linking HA with glycidyl ether. These reactions are under highly basic conditions. European Patent Application 0216453 published Apr. 1, 1987 describes esterification of hyaluronate salts with alkyl halides in organic media for use in drug delivery. The modified HA species show altered physical characteristics such as decreased solubility in water and increased solubility in organic solvents.
Dahl, et al., Anal. Biochem. 175, 397-407 (1988) and Curvall, et al., Carbohyd. Res. 41, 235-239 (1975) carried out hydrazinolysis of high molecular hyaluronate resulting in N-deacetylation and generation of a free amino group on the hyaluronate backbone. However, extensive degradation of HA resulted. The final products were heterogenous and none were fully characterized by spectroscopic analysis.
A mild and versatile chemical methodology that allows further coupling and crosslinking of HA is still needed. Furthermore, it would be most desirable if the methodology did not compromise the molecular weight integrity of the HA.
Accordingly, it is an object of the invention to provide a mild method for modifying hyaluronic acid without compromising the molecular weight of the HA molecule.
It is another object of the invention to provide a method for crosslinking of HA which can be either irreversible or reversible.
It is a further object to provide functionalized HA with a pendant functional group which acts as a versatile coupling site.
It is yet another object to provide a method for functionalizing and crosslinking HA so that resulting HA gel strength and type can be easily manipulated.
It is still another object to provide HA gels produced by these methods and which are useful for biological, medical, surgical and cosmetic applications.